Haralampos M Moutsopoulos, MD, FACP, FRCP, Master ACR
George E Fragoulis, MD
John H Stone, MD, MPH
Disclosures: Haralampos M Moutsopoulos, MD, FACP, FRCP, Master ACR Nothing to disclose. George E Fragoulis, MD Nothing to disclose. John H Stone, MD, MPH Grant/Research/Clinical Trial Support: Roche [vasculitis (tocilizumab)]; Genentech [IgG4-related disease (rituximab)]. Peter H Schur, MD Nothing to disclose. Paul L Romain, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Immunoglobulin G4-related disease (IgG4-RD) is an increasingly recognized immune-mediated condition comprised of a collection of disorders that share specific pathologic, serologic, and clinical features . These disorders were previously thought to be unrelated [2-4]. The commonly shared features include tumor-like swelling of involved organs, a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, and a variable degree of fibrosis that has a characteristic “storiform” pattern (picture 1). In addition, elevated serum concentrations of IgG4 are found in 60 to 70 percent of patients with IgG4-RD.
The majority of patients respond to glucocorticoids, particularly in early stages of disease. In some subsets of organ disease (eg, pancreatitis), glucocorticoid responsiveness has been considered one diagnostic criterion for the disorder.
Major presentations of this protean condition, which often affects more than one organ, include:
●Type 1 (IgG4-related) autoimmune pancreatitis (AIP)
●Salivary gland disease, which can present as major salivary gland enlargement or as sclerosing sialadenitis (the constellation of lacrimal, parotid, and submandibular gland enlargement was formerly termed “Mikulicz disease,” and isolated submandibular gland swelling was termed “Küttner’s tumor”)
●Orbital disease, often complicated by proptosis because of lacrimal gland enlargement, involvement of the extraocular muscles, or other orbital pseudotumor
●Retroperitoneal fibrosis, which frequently occurs in the larger context of chronic periaortitis and can often affect the ureters
●IgG4-related systemic disease
●IgG4-related sclerosing disease
●IgG4-related systemic sclerosing disease
●IgG4-related autoimmune disease
●IgG4-positive multiorgan lymphoproliferative syndrome
●Systemic IgG4-related plasmacytic syndrome
●Systemic IgG4-related sclerosing syndrome
●Multifocal idiopathic fibrosclerosis
This topic will provide an overview of the clinical manifestations, diagnosis, and treatment of IgG4-related disease and several of its component entities. Type 1 autoimmune pancreatitis (AIP, IgG4-related pancreatitis) and IgG4-related sclerosing cholangitis are discussed in detail separately (see "Autoimmune pancreatitis"), as are several of the other conditions associated with this disorder. (See appropriate topic reviews.)
DEFINITION AND HISTOLOGY — The hallmarks of immunoglobulin G4-related disease (IgG4-RD) are lymphoplasmacytic tissue infiltration with a predominance of IgG4-positive plasma cells and CD4+ T lymphocytes, usually accompanied by fibrosis, obliterative phlebitis, and elevated serum levels of IgG4 . A sizeable minority of patients (less than 40 percent) have normal serum IgG4 concentrations despite the presence of the classic histopathological changes in tissue . A good initial therapeutic response to glucocorticoids is characteristic, particularly if excessive tissue fibrosis has not supervened .
The fibrosis associated with IgG4-RD has a characteristic “storiform” pattern, typified by a cartwheel appearance of the arranged fibroblasts and inflammatory cells (picture 1 and picture 2) [7,10]. Modest tissue eosinophilia is also common (image 1).
EPIDEMIOLOGY — Immunoglobulin G4-related disease (IgG4-RD) generally occurs most commonly in middle-aged and older men. This is certainly true for conditions such as type 1 (IgG4-related) autoimmune pancreatitis (AIP), retroperitoneal fibrosis, IgG4-related tubulointerstitial nephritis (TIN), and many other organ manifestations. However, the sex distribution differs somewhat with regard to patients with involvement of organs of the head and neck. As examples, in patients with IgG4-related sialadenitis and IgG4-related ophthalmic disease, males and females appear to be affected more equally [3,11,12].
In a study of 114 patients with IgG4-RD, those with involvement limited to one of several regions (head and neck, thoracic, hepatopancreatobiliary, and retroperitoneal) and those with systemic involvement (more than one region) were compared with respect to various demographic and clinical features; the ages of patients in all groups were similar, with means from 59 to 68 years (ranges 42 to 79) . All the groups, other than the patients with head and neck involvement, were predominantly men (75 to 86 percent), but the group with only head and neck disease was nearly equally divided (48 percent men).
Beyond these general statements, the epidemiology of IgG4-RD requires further definition. Initially, study of the condition suffered from a lack of definitions, incomplete nomenclature, and underrecognition among clinicians and pathologists. These deficits are gradually being overcome and should facilitate more complete understanding of the disease epidemiology.
PATHOGENESIS — The pathogenesis of immunoglobulin G4-related disease (IgG4-RD) is poorly understood; findings consistent with both an autoimmune disorder and an allergic disorder are present [7,13-19]. IgG4 has been postulated to have a role in tolerance to allergens and in responses to certain infectious agents, but its physiologic role is poorly understood. A specific autoantigenic target has not been identified, and it is not clear whether the IgG4 antibodies are pathogenic . An emerging consensus holds that the IgG4 antibodies in this disease are not pathogenic, but rather represent a down-regulatory response to another primary process(es) . Elevations in serum and tissue IgG4 concentrations are not specific to IgG4-RD; they are also found in disorders such as multicentric Castleman’s disease, allergic disorders, the Churg-Strauss syndrome, sarcoidosis, and a large number of other conditions [22,23]. (See "IgG subclass deficiency", section on 'IgG4 deficiency' and "IgG subclasses: Physical properties, genetics, and biologic functions", section on 'Properties of IgG subclasses' and "Diagnostic evaluation of food allergy", section on 'Unvalidated methods' and "IgG subclasses: Physical properties, genetics, and biologic functions", section on 'Disorders associated with elevated subclass levels'.)
Findings in IgG4-RD suggesting autoimmunity have been particularly evident in patients with type 1 (IgG4-related) autoimmune pancreatitis (AIP), the prototypic IgG4-related disorder, including an association with a specific class II histocompatibility antigen genotype . Antinuclear antibodies are sometimes present, and autoantibodies have been described against lactoferrin and carbonic anhydrase II. Some studies have suggested a possible role for molecular mimicry involving Helicobacter pylori . Immune complex deposition in the pancreas, kidneys, and certain other affected tissues has been reported . However, autoantibody studies have been inconsistent, and there is no definitive evidence for a role of autoimmunity in this disease. (See "Autoimmune pancreatitis".)
Evidence for an allergic response includes elevated levels of Th2 cytokines in affected tissues and increased amounts of serum IgE . In addition, patients with IgG4-RD have an increased prevalence of allergic rhinitis and bronchial asthma . There are increased numbers of T regulatory cells (Tregs) in peripheral blood and increased levels of cytokines produced by Tregs, including interleukin (IL)-10 and transforming growth factor (TGF)-beta in affected tissues [16,17]. The Th2 cytokines, Tregs, and IL-10 help support IgG4 production [17,25]. Up to 40 percent of patients with IgG4-RD have a peripheral eosinophilia. However, two studies have demonstrated that circulating Th2 memory cells in IgG4-RD are restricted to a defined subset of subjects who have concomitant atopy [26,27].
CLINICAL MANIFESTATIONS — Immunoglobulin G4-related disease (IgG4-RD) can involve one or multiple organs. Patients often present with subacute development of a mass in the affected organ (eg, an orbital pseudotumor, a renal mass resembling renal cell carcinoma, nodular lesions in the lung) or diffuse enlargement of an organ (eg, the pancreas) [1,3,28]. Multiple organs are affected in 60 to 90 percent of patients with IgG4-RD [4,29]. The affected tissues share specific pathologic, serologic, and clinical features, regardless of the organ involved, in a manner analogous to the systemic involvement of sarcoidosis, another disorder with shared histopathologic features in the different tissues that are affected. Lymphadenopathy is common, and symptoms of asthma or allergy are present in approximately 40 percent of patients. Patients often feel well at the time of diagnosis and generally lack fever . However, patients with multiorgan disease often lose substantial amounts of weight—20 to 30 pounds (about 9 to 14 kg) over months—before the correct diagnosis is identified. IgG4-RD is often recognized incidentally based upon a radiologic finding or histopathologic examination of a tissue specimen.
The disorder has been viewed as uncommon, but manifestations of this syndrome are now increasingly recognized in nearly every organ system. Many of the initial observations regarding this condition were made in patients with autoimmune pancreatitis (AIP), which often presents as a pancreatic mass or as painless obstructive jaundice, and can be mistaken for pancreatic cancer. Additional reports have focused on patients with lacrimal and salivary gland involvement, formerly termed Mikulicz’s disease, which was once thought to be a subset of Sjögren’s syndrome (SS) (picture 3) [3,28]. Such patients may present, for example, with prominent parotid or submandibular gland enlargement. The terms IgG4-related dacryoadenitis and IgG4-related sialadenitis are now used in place of Mikulicz’s disease. IgG4-related dacryoadenitis and sialadenitis do not invariably occur together.
IgG4-RD associated disorders — Previously described conditions that represent manifestations of IgG4-RD and the nomenclature, when not otherwise indicated, include [3-5]:
●Type 1 (IgG4-related) AIP
●IgG4-related sclerosing cholangitis
●Mikulicz’s disease (IgG4-related dacryoadenitis and sialadenitis)
●Sclerosing sialadenitis (Küttner’s tumor, IgG4-related submandibular gland disease)
●Inflammatory orbital pseudotumor (IgG4-related orbital inflammation or orbital inflammatory pseudotumor)
●Chronic sclerosing dacryoadenitis (lacrimal gland enlargement, IgG4-related dacryoadenitis)
●A subset of patients with “idiopathic” retroperitoneal fibrosis (Ormond’s disease) and related disorders (IgG4-related retroperitoneal fibrosis, IgG4-related mesenteritis)
●Chronic sclerosing aortitis and periaortitis (IgG4-related aortitis or periaortitis)
●Riedel’s thyroiditis (IgG4-related thyroid disease)
●IgG4-related interstitial pneumonitis and pulmonary inflammatory pseudotumors (IgG4-related lung disease)
●IgG4-related kidney disease (including tubulointerstitial nephritis [TIN] and membranous glomerulonephritis [GN] secondary to IgG4-RD)
●IgG4-related midline destructive disease
Estimates of the relative frequency of different manifestations depend upon the particular perspective of the index illness being studied. As an example, a study of patients with AIP found frequent extrapancreatic involvement, including hilar lymphadenopathy (80 percent), extrapancreatic bile duct lesions (74 percent), lacrimal and salivary gland lesions (39 percent), hypothyroidism (22 percent), and retroperitoneal fibrosis (13 percent) . By contrast, AIP was found in only 17 percent of patients studied with IgG4-related lacrimal, parotid, or submandibular gland disease, and interstitial nephritis (17 percent) and interstitial pneumonitis (9 percent) were also seen among this group .
Lymphadenopathy — Asymptomatic IgG4-related lymphadenopathy is common, occurring in 80 percent of patients with AIP ; it is usually observed together with other clinical or laboratory manifestations of the syndrome, but may be the initial or only manifestation . In a study of 114 patients with varied organ involvement, lymphadenopathy was present in 41 percent of patients . Symptoms occasionally occur due to mass effect of the enlarging nodes; individual nodes are typically no more than 2 centimeters in diameter but may range up to 5 centimeters . Multiple groups of lymph nodes are usually involved; the mediastinal, hilar, intraabdominal, and axillary are most common and can be readily seen upon scanning with gallium-67 . The lymphadenopathy is generally non-tender and the nodes themselves are rubbery rather than hard.
Five histologic patterns may be seen, which all feature abundant IgG4-positive cells; the majority have eosinophil infiltration [7,33-35]. Histology is similar to other affected tissues, except that there is usually no sclerosis or phlebitis. The patterns include:
●Type I – Multicentric Castleman disease-like
●Type II – Follicular hyperplasia
●Type III – Interfollicular expansion
●Type IV – Progressive transformation of germinal center-like
●Type V – Nodal inflammatory pseudotumor-like
Patients with lymphadenopathy may exhibit elevated serum IgG4, serum IgG and IgE, polyclonal hypergammaglobulinemia, and elevations in the erythrocyte sedimentation rate (ESR).
The differential diagnosis in patients with generalized lymphadenopathy includes sarcoidosis, multicentric Castleman disease, infection (eg, tuberculosis), and lymphoma or other malignancy. IgG4-related lymphadenopathy is distinguished from these conditions by the modest lymph node enlargement, histologic distinctions on biopsy, lack of constitutional features, and the usually striking clinical response to glucocorticoids . Patients with bilateral hilar adenopathy may mimic sarcoidosis. (See "Evaluation of peripheral lymphadenopathy in adults" and "Clinical presentation and diagnosis of non-Hodgkin lymphoma" and "Epidemiology, pathologic features, and diagnosis of classical Hodgkin lymphoma" and 'Lung and pleural disease' below and "Multicentric Castleman's disease".)
Autoimmune pancreatitis — Type 1 (IgG4-related) AIP is the prototypical form of IgG4-RD. The prevalence of this condition in Japan has been estimated to be 0.82 per 100,000 persons, but this is likely to be an underestimate as clinical recognition of this disorder is growing [36,37]. Two types of AIP have been distinguished; the form associated with IgG4-RD is type 1 AIP, also denoted as lymphoplasmacytic sclerosing pancreatitis . AIP is discussed in detail separately. (See "Autoimmune pancreatitis".)
AIP has been estimated to account for 2 percent of patients with chronic pancreatitis . It often presents as a pancreatic mass or as painless obstructive jaundice and can be mistaken for pancreatic cancer. Some patients with type 1 AIP exhibit acute, recurrent, or chronic pancreatitis, and AIP is frequently associated with diabetes mellitus. Most patients have another concomitant IgG4-related condition, such as IgG4-related sclerosing cholangitis, lymphadenopathy, or salivary or lacrimal gland involvement. (See 'Clinical manifestations' above and "Autoimmune pancreatitis".)
The differentiation of AIP from adenocarcinoma of the pancreas is sometimes difficult on the basis of clinical presentations. Painless jaundice, for example, is common to both. Many patients have undergone Whipple procedures out of concern for pancreatic cancer. IgG4-positive plasma cells can also be found in the diseased pancreatic tissue in these conditions, although to a lesser degree than in AIP. Elevated serum IgG4 levels (>135 mg/dL) can also be seen in some patients with pancreatic cancer, although they are usually less than twice the upper limit of normal; thus, increased IgG4 serum levels alone cannot be used to exclude a diagnosis of pancreatic malignancy . Radiologic features of type I AIP include diffuse enlargement of the pancreas, leading to the descriptor “sausage-shaped” pancreas, and a halo of edema surrounding the organ. Both of these features are appreciated most readily on abdominal computerized tomographic (CT) scanning.
IgG4-related sclerosing cholangitis — A form of sclerosing cholangitis that is clinically distinct from primary sclerosing cholangitis may occur as part of the IgG4-RD. IgG4-related sclerosing cholangitis is the most frequent extrapancreatic manifestation of type 1 AIP (IgG4-related), present in over 70 percent of such patients . It also rarely occurs in the absence of pancreatitis. Distinctions between primary sclerosing cholangitis and IgG4-related sclerosing cholangitis are crucial because of the drastically different prognoses in these conditions. Unfortunately, the clinical distinction between primary sclerosing cholangitis and/or cholangiocarcinoma and IgG4-related sclerosing cholangitis can be difficult because biopsies performed via endoscopic retrograde cholangiopancreatography (ERCP) are seldom deep enough to define the histopathological features of IgG4-RD [17,39]. Although clearly defined diagnostic criteria for IgG4 sclerosing cholangitis are lacking, differentiation from primary sclerosing cholangitis is based upon tissue biopsy with infiltrates of IgG4+ plasma cells and severe interstitial fibrosis, increased IgG4 serum levels, and characteristic responsiveness to glucocorticoids. The presence of clinical manifestations of IgG4-RD in extra-biliary organs can also be an important clue to the presence of IgG4-RD [40,41].
One study suggests that patients with cholangiocarcinoma, as opposed to IgG4-related sclerosing cholangitis, are more likely to present with obstructive jaundice, an enlarged pancreas, and lymphadenopathy. Cholangiocarcinoma patients also generally have higher serum bilirubin concentrations, higher levels of CA 19-9, and complete obstruction of the hilar or bile ducts as demonstrated by ERCP. A cutoff higher than the standard upper limited of normal for serum IgG4 concentrations (ie, >135 mg/dL) may also be useful in distinguishing IgG4-RD from cholangiocarcinoma; the higher the serum IgG4 concentration, the greater the likelihood that the patient has IgG4-RD rather than a biliary tract malignancy . (See "Autoimmune pancreatitis", section on 'Biliary tract manifestations' and "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Differential diagnosis' and "Clinical manifestations and diagnosis of cholangiocarcinoma".)
Salivary and lacrimal gland involvement — Salivary gland involvement is a common feature of IgG4-RD. Patients may present with enlargement of lacrimal and salivary glands (parotid and/or submandibular) or with chronic sclerosing sialadenitis and unilateral or bilateral submandibular gland enlargement . These entities were previously called Mikulicz disease (or syndrome) and Küttner’s tumor, respectively, and were often erroneously considered to be subcategories of SS (picture 3) [11,20,43-48]. Many of the patients previously described as having SS in association with AIP and IgG4-RD may have had one of these conditions rather than true SS. (See "Diagnosis and classification of Sjögren's syndrome", section on 'Mikulicz syndrome and IgG4-related disease' and "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging".)
Nearly 40 percent of patients with IgG4-related pancreatitis also have salivary or lacrimal gland involvement, while AIP may be seen in only 17 percent of patients presenting with sialadenitis [11,30]. Sialadenitis often presents prior to AIP in patients who develop both conditions . Unlike AIP and other forms of IgG4-RD, patients with salivary and lacrimal involvement include comparable numbers of both men and women [11,12]. The pathologic findings are typical of those in other patients with IgG4-RD, including the lymphoplasmacytic infiltrate with IgG4-positive cells, sometimes with obliterative phlebitis and fibrosis (picture 4 and picture 5 and image 2 and image 3 and image 4 and image 5) . Increased IgG4 and IgE serum levels are also present. These histopathologic and laboratory findings distinguish IgG4-related sialadenitis from SS. Low complement levels may be seen in either condition.
Patients who fulfill criteria for both SS and IgG4-RD have been identified. Increased IgG4 serum levels (>135mg/dL) were present in 7.5 percent of a cohort of 133 patients with well-defined primary SS . The patients with elevated levels of IgG4 displayed a higher frequency of IgG4-RD clinical features (autoimmune pancreatitis, autoimmune cholangitis, and interstitial nephritis) and lower rates of antinuclear, anti-Ro/SSA, and anti-La/SSB autoantibodies. In addition, 2.3 percent of patients studied had increased numbers of IgG4 (+) plasmacytes in labial minor salivary gland biopsies. These patients may represent a distinct subgroup of SS or, most probably, are IgG4-RD patients misclassified as having SS.
The clinical features that characterize IgG4-related sialadenitis and also help to distinguish it from SS include :
●Fewer patients with dry mouth, dry eyes, or arthralgias (38, 33, and 16 percent versus 87, 94, and 48 percent, respectively). Despite marked lacrimal and salivary gland enlargement, these patients experience relatively mild dryness of the eyes and of the mouth.
●A higher frequency of allergic rhinitis and bronchial asthma (41 and 14 percent versus 7 and 3 percent, respectively).
●A higher frequency of AIP and interstitial nephritis (17 and 17 percent versus 0 and 7 percent, respectively).
●Low frequencies of autoantibodies, including rheumatoid factor, antinuclear antibodies, anti-SSA, and anti-SSB (27, 23, 2, and 0 percent versus 87, 90, 100, and 100 percent, respectively).
Patients with IgG4-related ophthalmic disease, primarily involving the lacrimal gland (IgG4-related dacryoadenitis), have also been identified [51,52]. Many exhibited bilateral involvement, and concurrent salivary gland involvement was common. Histologic and serologic findings are similar to those seen in patients with sialadenitis and in other tissues. IgG4-RD also appears to account for 25 to 50 percent of orbital pseudotumors and is also recognized as a cause of orbital myositis (IgG4-related orbital myositis) [53,54].
It is not certain whether IgG4-RD predisposes to the development of ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphomas or other lymphomas, but several cases have been reported that have raised this concern [55-57]. Additional study is required.
Retroperitoneal fibrosis and related disorders — In several small case series, a variable proportion of patients with idiopathic retroperitoneal fibrosis exhibits histologic and serologic changes consistent with IgG4-RD [58-62]. Chronic inflammatory and fibrotic change may be present and can involve regional tissues; it may cause an obstructive uropathy. In some cases, the syndrome is responsive to glucocorticoids. The diagnosis of IgG4-RD in this setting can be challenging because of the advanced fibrotic changes typically observed in this condition. Retroperitoneal fibrosis is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis" and "Treatment of retroperitoneal fibrosis".)
All 14 of the published cases of IgG4-related retroperitoneal fibrosis collected in one review exhibited involvement of other organs, including the pancreas (11 patients), salivary glands (3 patients), lymph nodes (2 patients), one affecting the pituitary gland, and one with mediastinal periaortitis . However, cases of isolated IgG4-related retroperitoneal fibrosis have also been described .
Cases of patients with sclerosing mesenteritis, sclerosing mediastinitis, and multifocal fibrosclerosis have also been reported associated with IgG4-RD [64-66]. (See "Sclerosing mesenteritis", section on 'Autoimmunity' and "Fibrosing mediastinitis", section on 'Other precipitants'.)
Aortitis and periaortitis — IgG4-RD has been recognized as one of the causes of noninfectious aortitis . A series of patients with thoracic lymphoplasmacytic aortitis or with inflammatory abdominal aortic aneurysms and abdominal periaortitis has been identified in retrospective pathologic studies of patients who had undergone aortic resections [61,67,68]. (See "Epidemiology, risk factors, pathogenesis and natural history of abdominal aortic aneurysm", section on 'Pathogenesis'.)
●IgG4-related thoracic aortitis – In a study of 638 patients who underwent thoracic aortic resection over a five-year period in a North American hospital, three of four patients with lymphoplasmacytic aortitis exhibited histology characteristic of IgG4-RD . These three patients represented 9 percent of the 33 cases identified in the study with noninfectious aortitis, or 0.5 percent of the entire series of thoracic aortic resections. These three patients and three other reported patients were all men between the ages of 65 and 74 .
Similarly, in a series of 125 patients reported from a hospital in Japan, two patients with IgG4-related aortitis were identified among 120 patients with thoracic aortic resections (1.6 percent) . Three additional patients with atherosclerotic changes and without extra-aortic involvement by IgG4-RD also had similar infiltrates of IgG4-positive plasma cells. Whether patients with prominent atherosclerotic changes should also be included among patients with IgG4-RD remains uncertain [61,69].
●IgG4-related abdominal aortitis – Four of 10 patients with inflammatory abdominal aortic aneurysms identified at a medical center in Japan over a 15-year period had findings consistent with IgG4-RD, including infiltration with IgG4-positive plasma cells and elevated serum levels of IgG4 . Patients ranged in age from 58 to 72 years. Inflammatory abdominal aortitis may be associated with retroperitoneal fibrosis .
Thyroid disease — Two forms of thyroid involvement in IgG4-RD have been described, including Reidel’s thyroiditis (IgG4-related thyroid disease) and the fibrous variant of Hashimoto’s thyroiditis [70,71]. Reidel’s thyroiditis is discussed in detail elsewhere. (See "Infiltrative thyroid disease", section on 'Riedel's thyroiditis'.)
Lung and pleural disease — Multiple reports have documented IgG4-related pulmonary disease, which may be asymptomatic or present with cough, hemoptysis, dyspnea, pleurisy, or chest pain; pseudotumors and interstitial pneumonia have been associated with AIP [72-76]. Visceral or parietal pleural thickening may occur . The affected tissues exhibit characteristic lymphoplasmacytic infiltrates enriched in IgG4-positive plasma cells, interspersed with abundant storiform fibrosis (image 6). Obliterative arteritis is more common in the lung than in other organs affected by IgG4-RD . Four patterns of lung involvement have been described [76,77]:
●Alveolar interstitial (with honeycombing, bronchiectasis, and diffuse ground-glass opacities)
●Round-shaped, ground-glass opacities
IgG4-RD may mimic sarcoidosis [78,79]. In one study of patients suspected of having sarcoid with bilateral hilar adenopathy and/or lung nodules on CT of the chest, patients with IgG4-RD were identified among a subset with elevated serum IgG4; they exhibited significantly higher levels of bronchoalveolar lavage IgG4, IgG4/IgG, and IgG4/IgG3 compared with those with normal serum IgG4 levels .
Interstitial pneumonitis associated with IgG4-RD is discussed separately. (See "Interstitial lung disease associated with Sjögren's syndrome: Clinical manifestations, evaluation, and diagnosis", section on 'IgG4-related systemic disease'.)
Renal disease — Individual cases and case series have described renal involvement in patients with IgG4-RD; the most common finding is tubulointerstitial nephritis (TIN) [80-83]. Affected patients are primarily middle-aged and older men, and histopathology and other laboratory characteristics are similar to those observed in patients with autoimmune pancreatitis (AIP) . The histologic findings include lymphoplasmacytic infiltration of the renal interstitium and the presence of fibrosis (image 7). Immunohistochemistry of renal biopsy tissue demonstrates increased numbers of IgG4-positive plasma cells (image 8). Nodular lesions mimicking renal carcinoma may be seen.
In a study of 153 patients with suspected IgG4-related disease, retrospectively collected from multiple medical centers in Japan, 23 patients (15 percent) were identified with TIN secondary to IgG4-RD, all but one of whom (96 percent of TIN patients) exhibited involvement of other organs . These extrarenal manifestations included sialadenitis (83 percent), lymphadenopathy (44 percent), AIP (39 percent), dacryoadenitis (30 percent), lung lesions (26 percent), and others in individual patients. In addition to TIN, 3 of the 23 patients also had mild mesangioproliferative glomerulonephritis (GN), and one each had findings of membranous nephropathy and of focal segmental endocapillary hypercellularity.
Symptoms were usually associated with the extrarenal manifestations, rather than the renal abnormalities, although edema was seen in two patients. Renal changes were recognized due to urinary abnormalities, renal dysfunction, and/or imaging abnormalities, including renal parenchymal lesions on computerized tomography and increased renal uptake with gallium citrate scintigraphy.
IgG4-related membranous nephropathy is much less frequent than IgG4-related TIN, and these sometimes occur together . In a series of nine patients with IgG4-related membranous GN, five of the patients had concurrent IgG4-related TIN, and seven exhibited extrarenal involvement by IgG4-RD [84,85]. None of the patients with IgG4-related disease were positive for phospholipase A2 receptor on biopsy, although it is present in a majority of patients with primary membranous GN. (See "Causes and diagnosis of membranous nephropathy", section on 'IgG4-related disease'.)
Other involved organs and tissues — Involvement of other organs and tissues by IgG4-RD, which has been described in additional case reports and small case series, includes:
●Skin disease, including a subset of cutaneous pseudolymphoma. The lesions typically appear on the scalp, face, neck, and pinna of the ear [86-88].
●IgG4-hepatopathy, resembling autoimmune hepatitis, and hepatic inflammatory pseudotumor [89,90].
●Lymphoplasmacytic gastritis associated with autoimmune pancreatitis .
●Sclerosing mastitis and inflammatory pseudotumors of the breast [92,93].
●Hypopituitarism with IgG4-related hypophysitis [94,95].
●Constrictive pericarditis [3,99,100].
●Nasopharyngeal disease [101,102].
●Midline-destructive lesion .
DIAGNOSIS — The diagnosis of immunoglobulin G4-related disease (IgG4-RD) is based upon biopsy findings demonstrating the characteristic histopathologic findings and immunohistochemical staining. These findings include lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and lymphocytes, accompanied by fibrosis that has storiform features and often by obliterative phlebitis (image 9). A modest tissue eosinophilia is often present. Serum IgG4 levels should be measured, and isolated elevated levels are a significant aid in diagnosis, although they are not diagnostic. The histopathological and immunohistochemical staining features of IgG4-RD are strikingly similar in different tissues, regardless of the organ or tissue involved. (See 'Diagnostic criteria' below.)
Indications for diagnostic evaluation — The possibility of IgG4-RD should be considered in patients with one of the characteristic patterns of organ or tissue involvement. (See 'IgG4-RD associated disorders' above.)
Patients at high risk for having IgG4-RD are those with any of the following:
●Pancreatitis of unknown origin
●Bilateral salivary and/or lacrimal gland enlargement
●Orbital pseudotumor or proptosis
The likelihood of IgG4-RD for patients presenting with at least one of these conditions is significantly increased if high serum levels of IgG4, allergic symptoms, and/or other fibrotic processes are also present.
Diagnostic studies — The diagnosis of IgG4-RD requires characteristic findings upon biopsy of affected tissue, but additional organ involvement may be possible to identify through a careful history, physical examination, routine laboratory testing, and selected imaging studies. (See 'Clinical manifestations' above and 'Diagnosis' above.)
We obtain the following testing for establishing the initial diagnosis:
●Tissue biopsy – The specific procedure depends upon what target organ will be biopsied and whether a discrete mass is present. A core needle biopsy is often adequate, but fine-needle aspirates do not provide adequate tissue [7,12]. In the presence of abnormal histopathology characteristic of the syndrome, we generally do not perform additional biopsies of other organs, particularly if improvement in these other areas has occurred with glucocorticoid treatment.
●Serum IgG4 – The serum IgG4 level was elevated above the upper limit of normal (>135 mg/dL) in 86 percent of 114 patients in one study . The degree of IgG4 elevation correlates imperfectly with the degree of disease activity, but is often a useful parameter to follow in individual patients. The serum IgG4 concentration tends to increase with the number of organs involved and usually decreases after treatment with glucocorticoids [7,104].
One study of serum IgG4 concentration measurements at a single institution over a 10-year period (2001 to 2011) reported the test characteristics for this assay . During that time period, 190 unique patients had elevated serum IgG4 concentrations (>135 mg/dL). The comparison population consisted of 190 other randomly selected patients with normal IgG4 concentrations. The study found the following:
•Sixty-five of the 72 patients with either definite or probable IgG4-RD had elevated serum IgG4 concentrations (mean: 405 mg/dL; range 140 to 2000 mg/dL), for a sensitivity of 90 percent.
•Among the 308 subjects without IgG4-RD, 125 had elevated IgG4 levels (mean: 234 mg/dL; range 135 to 1180 mg/dl) and 183 had normal IgG4 concentrations, for a specificity of 60 percent.
•The negative predictive value of a serum IgG4 assay in these groups was 96 percent, but the positive predictive value was only 34 percent.
•Doubling the cutoff for IgG4 improved the specificity (91 percent), but decreased the sensitivity to an unacceptably low 35 percent. Analysis of the serum IgG4/total IgG ratio did not improve these test characteristics.
●Blood plasmablasts as biomarkers - Blood plasmablast concentrations may be a better biomarker than the serum IgG4 concentration, both for the purposes of diagnosis and following disease activity [106,107]. Patients with IgG4-RD who were untreated at the time their blood was sampled were found to have dramatic elevations of blood plasmablast concentrations. Plasmablasts were identified through flow cytometry of peripheral blood, gating on cells that were CD19lowCD38+CD20-CD27+ . The investigators evaluated 37 untreated patients with IgG4-RD and a total of 35 controls, including both healthy individuals (n = 14) and patients with other active inflammatory diseases who had not yet received treatment (n = 21). The results are summarized below:
•The IgG4-RD patients had significantly elevated total plasmablast counts (median: 4,698/mL; range: 610 to 79,524/mL) compared with both untreated disease controls (median: 592/mL; range: 19 to4294/mL) and healthy controls (median: 94/mL; range: 1 to 653/mL).
•Thirteen IgG4-RD patients (36 percent) had normal serum IgG4 concentrations (mean: 60mg/dL; range: 5 to 123 mg/dL; normal: <135mg/dL). However, the median plasmablast count was not significantly lower in that subset with normal serum IgG4 concentrations compared with those with elevated serum IgG4: 3784/mL versus 5155/mL, respectively (p = 0.242).
•Among the 12 rituximab (RTX)-treated patients, the median plasmablast level during disease flare was 6356/mL (range: 1123 to 41,589/mL), declining to 1419/ml (range: 386/mL to 4150/mL) during remission.
These studies of circulating plasmablasts confirm that these cells are elevated to dramatically high levels in patients with active IgG4-RD, even in patients with normal serum IgG4 concentrations. Plasmablast counts therefore are a potentially useful biomarker for diagnosis, assessing response to treatment, and determining the appropriate time for retreatment. Additional studies of plasmablasts are required, particularly prospective investigations that focus on IgG4+ plasmablasts, the response of these cells to treatment, and their ability to predict disease relapses.
Diagnostic criteria — A consensus statement from a multinational, multidisciplinary group of experts on IgG4-RD describes guidelines for the diagnosis of the disease and the histopathologic findings important in making the diagnosis . Well-defined diagnostic criteria had previously been proposed only for autoimmune pancreatitis (AIP). The histopathological findings of a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis are critical features for establishing the diagnosis (picture 1). The presence of these findings, often together with mild tissue eosinophilia, is strongly suggestive if accompanied by increased numbers of IgG4-positive plasma cells. (See "Autoimmune pancreatitis", section on 'Diagnosis'.)
The number of IgG4-positive plasma cells per high-power field (HPF) that is regarded as consistent with or suggestive of IgG4-RD varies somewhat from tissue to tissue. Tissue IgG4-positive cell counts and the ratios of IgG4- to IgG-positive cells are considered secondary in importance to the histopathological appearance of the tissue [3,7,12,45,108]. Generally, the minimum for making the diagnosis for most tissues is from 30 to 50 IgG4-positive cells/HPF. However, in some organs or tissues, including the kidney and others, only 10 IgG4-positive plasma cells/HPF may be sufficient.
The diagnosis cannot be predicated entirely upon the number of IgG4-positive plasma cells, because a large number of other entities can have such cells. Similarly, the diagnosis of IgG4-RD cannot be based upon serum concentrations of IgG4 alone, because serum IgG4 concentrations are neither sufficiently sensitive nor specific for this disease. Thus, we strongly prefer confirmation of the diagnosis by biopsy of an involved organ whenever this is possible. Blood plasmablast concentration measurements, particularly those for IgG4+ plasmablasts, are not widely available.
Postdiagnostic evaluation — We obtain the following testing for establishing the extent of disease following the initial diagnosis:
●Imaging studies – We generally obtain a computed tomography (CT) scan of the chest, abdomen, and pelvis in patients diagnosed with IgG4-RD, because of the frequency of subclinical disease. Selected patients require additional imaging studies, particularly if disease in the orbits is suspected. Where available, positron emission tomographic (PET) scanning can also be highly effective in determining the extent of disease and should be considered at baseline.
Characteristic imaging findings on CT, magnetic resonance imaging (MRI), or PET scanning include diffuse and focal organ infiltration and encasement by inflammatory and fibrotic tissue .
●Urinalysis – Asymptomatic proteinuria may be an indication of subclinical IgG4-related tubulointerstitial nephritis (TIN).
●Serum complement levels – Serum C3 and C4 concentrations are typically low, often profoundly so, in the setting of TIN. Following serum complement concentrations in such patients can be a useful means of gauging response to therapy.
●Markers of allergic disease – Markers of allergic disease such as serum IgE concentrations and the peripheral eosinophil count, should be tested at baseline and, if abnormal, at follow-up.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of immunoglobulin G4-related disease (IgG4-RD) is broad and depends upon the specific site of involvement and clinical presentation. (See appropriate heading above and appropriate topic reviews)
TREATMENT — The optimal treatment for immunoglobulin G4-related disease (IgG4-RD) has not been established. Our approach to treatment of IgG4-RD is based upon observational data, including case reports and case series, many of which have focused on patients with autoimmune pancreatitis (AIP) . A growing number of reports support the efficacy of B cell depletion with rituximab in this condition [110-112]. However, no randomized trials have evaluated approaches to the treatment of either IgG4-RD overall or any organ-specific disease subset such as AIP. (See "Autoimmune pancreatitis", section on 'Treatment' and "Autoimmune pancreatitis", section on 'Glucocorticoids'.)
Most patients respond to glucocorticoids within several weeks, typically with symptomatic improvement, reductions in the size of masses or organ enlargement, improvement in organ function, and often a decrease in serum levels of IgG4. However, some require a few months to respond, and there are some patients who relapse and others who respond less well or not at all initially. Those who respond poorly may include patients with more advanced fibrotic changes, but these patients have not been well-defined. An IgG4-RD Responder Index has been developed and employed in clinical investigations and in laboratory-based biomarker studies using clinical data . The treatment of AIP and the evidence supporting the use of these therapies in AIP are discussed in detail elsewhere. (See "Autoimmune pancreatitis", section on 'Treatment'.)
Patients who are symptomatic from their organ involvement at the time of the diagnosis often benefit from treatment. Examples of such symptomatic involvement include patients with lacrimal gland swelling or other orbital pseudotumors, who may have significant proptosis; those with submandibular or parotid gland swelling, who may have pain from their glandular enlargement or concern about cosmetic issues; those with renal involvement, who may have kidney dysfunction due to tubulointerstitial nephritis; and those with type I AIP or retroperitoneal fibrosis, who may have hydronephrosis, pain, or other manifestations of their organ involvement. All of these patients need to be treated. By contrast, for a subset of patients such as those who have mild lymphadenopathy or incidentally-detected lung nodules, watchful waiting may be appropriate.
We suggest beginning treatment with prednisone, usually at a dose of approximately 40 mg/day. A response is frequently seen within two to four weeks and often sooner. Once a significant response is clinically evident in the affected organ system, we begin to gradually taper the dose of glucocorticoids, with a planned reduction over a two-month period, as tolerated, and the goal of discontinuing the medication entirely.
In patients who are resistant to glucocorticoids or who are unable to have their dose reduced sufficiently (usually to below 10 mg/day of prednisone) to avoid adverse effects of the medication due to chronic use, we use rituximab (1 gram IV every fifteen days for a total of two doses). Case series suggest that B cell depletion therapy is an effective treatment in many of the patients with IgG4-RD that is refractory to glucocorticoids and other medications [110-112]. B cell depletion leads to the targeted reduction, often swiftly, of serum IgG4 concentrations, with relative preservation of the concentrations of other immunoglobulins and immunoglobulin subclasses. This suggests that B cell depletion achieves its effects at least in part by interfering with the repletion of short-lived plasma cells that are producing IgG4. Once these IgG4-producing cells disappear, they are not repleted following the anti-CD20 therapy because the pool of circulating B cells has been depleted. Rituximab also leads even more swiftly to steep declines in blood plasmablast concentrations [106,107].
If rituximab is not available, either azathioprine (2 mg/kg/day) or mycophenolate mofetil (up to 2.5 g/day as tolerated) are reasonable choices for second-line agents that have potential as glucocorticoid-sparing therapies. However, the effects of these glucocorticoid-sparing medications in IgG4-RD have not been evaluated adequately to clearly define their role relative to other agents. (See "Autoimmune pancreatitis", section on 'Treatment' and "Autoimmune pancreatitis", section on 'Immunomodulatory drugs'.)
PROGNOSIS — The natural history of immunoglobulin G4-related disease (IgG4-RD) has not been well-defined. A minority of patients improve at least temporarily without treatment, but the majority of these relapse and most patients have chronic disease that progresses at variable rates [7,110]. Causes of significant morbidity and mortality in untreated patients include cirrhosis and portal hypertension; retroperitoneal fibrosis; complications from aortic aneurysms, including dissection; biliary obstruction; diabetes mellitus; and others [40,59,67,110,114]. A subset of patients have subacute constitutional symptoms marked by fatigue and weight loss that may be substantial over months, on the order of 20 or 30 pounds. Sustained benefit may be observed in treated patients, but relapses are common after discontinuation of therapy. Additional organs and tissues may become involved over time, sometimes despite apparently effective treatment. Additional studies of long term prognosis are needed.
Risk of malignancy — Several types of lymphoma have been reported in patients with IgG4-RD, both in Japan and in North America [7,51,55,115,116]. In the study in North America, which involved 111 patients with IgG4-RD (91 percent with autoimmune pancreatitis [AIP]), three cases of non-Hodgkin lymphoma were found three to five years after the diagnosis of IgG4-RD . The standardized incidence ratio was 16.0 (95% CI 3.3-45.5), suggesting an increased risk of non-Hodgkin lymphoma among this group of patients referred to an academic medical center with special interest in this disorder. Further studies are required to better define the degree of risk and the effect of treatment upon such risk, if present.
In one series of 108 Japanese patients with IgG4-related pancreatitis, 18 cancers were found in 15 patients (14 percent); the median follow-up was 3.3 years . At the time of diagnosis of the pancreatitis, the relative risk (RR) of cancer was significantly increased compared with age- and sex-matched controls (RR 4.9, 95% CI 1.7-14.9); the risk was highest in the year following diagnosis. Gastric cancers were the most common; other sites included lung, prostate, colon, non-Hodgkin lymphoma, bile duct, and thyroid. In six of eight patients whose cancer was assessed histologically before treatment with glucocorticoids for the pancreatitis, IgG4-positive plasma cell infiltrates were found in the cancer tissue. None of these patients experienced relapse of their IgG4-related pancreatitis after successful treatment of their cancers, raising the question of whether IgG4-RD may occur as a paraneoplastic syndrome in some patients.
Several cases of pancreatic cancer and cases of salivary duct carcinoma, pulmonary adenocarcinoma, small cell carcinoma of the lung, and gastrointestinal clear cell sarcoma have also been reported . Additional study is required to determine the degree, if any, of increased risk for these and other malignancies in affected patients.
SUMMARY AND RECOMMENDATIONS
●Immunoglobulin G4-related systemic disease (IgG4-RD) is an increasingly recognized syndrome of unknown etiology, most often occurring in middle-aged and older men, which is comprised of a collection of disorders that share specific pathologic, serologic, and clinical features. Several of the manifestations typically occur in the same patient; these findings were previously thought to be unrelated and include (see 'Clinical manifestations' above and 'IgG4-RD associated disorders' above):
•Mikulicz’s disease and sclerosing sialadenitis (Küttner’s tumor), inflammatory orbital pseudotumor, and chronic sclerosing dacryoadenitis (see 'Salivary and lacrimal gland involvement' above)
•Idiopathic retroperitoneal fibrosis and related disorders (see 'Retroperitoneal fibrosis and related disorders' above)
•Chronic sclerosing aortitis and periaortitis (see 'Aortitis and periaortitis' above)
•Riedel’s thyroiditis and a subset of Hashimoto’s thyroiditis (see 'Thyroid disease' above)
•IgG4-related interstitial pneumonitis and pulmonary inflammatory pseudotumors (see 'Lung and pleural disease' above)
•IgG4-related renal disease, particularly tubulointerstitial nephritis (TIN) (see 'Renal disease' above)
●The hallmarks of IgG4-RD are lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and small lymphocytes, which may be accompanied by fibrosis, obliterative phlebitis, and, in the majority of patients, elevated serum levels of IgG4. Patients often present with subacute development of a mass in the affected organ or diffuse enlargement of an organ. Lymphadenopathy is common, and symptoms of asthma or allergy may be present. A good initial therapeutic response to glucocorticoids is also characteristic. (See 'Definition and histology' above and 'Pathogenesis' above and 'Lymphadenopathy' above.)
●The diagnosis of IgG4-RD is based upon biopsy findings demonstrating the characteristic histopathology. Serum IgG4 levels should be measured, and isolated elevated levels are a significant aid in diagnosis, although they are not diagnostic. Additional organ involvement may be identified through a careful history, physical examination, routine laboratory testing, and selected imaging studies. (See 'Diagnosis' above and 'Indications for diagnostic evaluation' above and 'Diagnostic studies' above.)
●We suggest beginning treatment with glucocorticoids (Grade 2B). We generally initiate therapy with prednisone (40 mg/day), which is then tapered as tolerated over a two-month period. Responses are characterized by symptomatic improvement, reductions in the size of masses or organ enlargement, improvement in organ function, and often a decrease in serum levels of IgG4. In patients who do not respond to up to 40 mg/day of prednisone or who cannot be tapered to less than 10 mg daily, we use rituximab. (See 'Treatment' above and "Autoimmune pancreatitis", section on 'Treatment'.)
●The natural history and prognosis are not well-described. Spontaneous improvement can be seen, but disease often recurs without treatment. Most patients respond initially to therapy with glucocorticoids, but relapses are common following discontinuation of therapy. Significant organ dysfunction may arise from uncontrolled and progressive inflammatory and fibrotic changes in affected tissues. The possibility of increased risk of malignancy in patients with IgG4-RD requires further study. (See 'Prognosis' above and 'Risk of malignancy' above.)
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